These studies continue to evaluate the effects of radiation therapy and chemotherapy as they relate to the organization of the hematopoietic stem cell compartment and to bone marrow transplantation (BMT). The bone marrow is an important dose limiting cell renewal tissue for both wide field irradiation and chemotherapy. These studies will explore the number and pedigree of the cells transplanted as these parameters relate to engraftment, survival and long term hematopoietic function in recipient animals. This should allow further definition of the limited proliferative capacity of the bone marrow stem cell compartment. Two of the major problems in BMT are minimizing the potential toxicities of preparing the recipient for transplantation while continuing to optimize long term engraftment. High dose cyclophosphamide and total body irradiation (TBI) are used by most centers to prepare recipients for BMT although busulfan has been substituted for TBI in some institutions. The organ specific toxicities of TBI and busulfan will be compared. Experiments will evaluate whether the addition of cyclophosphamide will allow reduction in the doses of TBI or busulfan required to maintain engraftment at equivalent or lower toxicity as compared to the use of TBI or busulfan alone. Engraftment and survival decrease following transplantation of T cell depleted marrow as the genetic differences between host and recipient increase. The role of accessory cells and factor secretion in the positive regulation of engraftment may also be mediated by residual recipient marrow cells and alternative transplantation regimens to treat the recipient marrow will be tested. These will include increasing the dose of TBI, the addition of cytotoxic agents along with TBI, and the treatment of recipient animals with monoclonal antibodies to T cells or natural both to improve engraftment of T depleted marrow as well as to minimize the toxicity of TBL. All of these studies should allow improvement of engraftment through alterations in the marrow or in preparation of the recipient.